5-Meth­oxy-1-[(5-meth­oxy-1H-indol-2-yl)meth­yl]-1H-indole

Mohamed I Attia; Nasser R El-Brollosy; Hazem A Ghabbour; Suhana Arshad; Hoong-Kun Fun

doi:10.1107/S1600536812009257

. 2012 Mar 7;68(Pt 4):o971. doi: 10.1107/S1600536812009257

5-Methoxy-1-[(5-methoxy-1H-indol-2-yl)methyl]-1H-indole

Mohamed I Attia ^a, Nasser R El-Brollosy ^a, Hazem A Ghabbour ^a, Suhana Arshad ^b, Hoong-Kun Fun ^b,^*,^‡

PMCID: PMC3343946 PMID: 22590027

Abstract

In the title compound, C₁₉H₁₈N₂O₂, the two indole ring systems are essentially planar [maximum deviation = 0.015 (2) Å in both indole ring systems] and make a dihedral angle of 72.17 (7)° with each other. In the crystal, the molecules are linked into a zigzag chain along the a axis via N—H⋯O hydrogen bonds.

Related literature

For the biological activity of melatonin (MLT), see: Csernus & Mess (2003 ▶); Nosjean et al. (2000 ▶); Blask et al. (2002 ▶); Genovese et al. (2005 ▶); Mills et al. (2005 ▶); Peres (2005 ▶); Sofic et al. (2005 ▶); Witt-Enderby et al. (2006 ▶). For related structures, see: Narayanan et al. (2011 ▶); Deng et al. (2011 ▶). For the synthesis, see: Attia et al. (2008 ▶).

Experimental

Crystal data

C₁₉H₁₈N₂O₂
M _r = 306.35
Monoclinic,
a = 9.4446 (5) Å
b = 19.5625 (8) Å
c = 8.6657 (5) Å
β = 98.903 (4)°
V = 1581.78 (14) Å³
Z = 4
Cu Kα radiation
μ = 0.68 mm⁻¹
T = 296 K
0.92 × 0.20 × 0.06 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2009 ▶) T _min = 0.575, T _max = 0.961
9421 measured reflections
2584 independent reflections
2087 reflections with I > 2σ(I)
R _int = 0.041

Refinement

R[F ² > 2σ(F ²)] = 0.046
wR(F ²) = 0.133
S = 1.06
2584 reflections
215 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: APEX2 (Bruker, 2009 ▶); cell refinement: SAINT (Bruker, 2009 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812009257/is5084sup1.cif

e-68-0o971-sup1.cif^{(25.9KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812009257/is5084Isup2.hkl

e-68-0o971-Isup2.hkl^{(126.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812009257/is5084Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H1N2⋯O1ⁱ	0.88 (2)	2.24 (3)	3.037 (2)	151 (2)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors thank the Deanship of Scientific Research and the Research Center of the College of Pharmacy, King Saud University, for supporting this study. HKF and SA thank Universiti Sains Malaysia (USM) for the Research University Grant (1001/PFIZIK/811160). SA also thanks the Malaysian Government and USM for the Academic Staff Training Scheme (ASTS) award.

supplementary crystallographic information

Comment

Melatonin (N-acetyl-5-methoxytryptamine, MLT) is primarily produced by the pineal gland in the brain with a marked circadian rhythm normally peaking in the dark to regulate sleep. MLT acts through activation of two G-protein-coupled receptors, designated as MT₁ and MT₂ (Csernus & Mess, 2003). In addition, a low-affinity putative MLT binding site called MT₃ has been recently characterized as a melatonin-sensitive form of the human enzyme quinine reductase 2 (Nosjean et al., 2000). MLT has found widespread use in the treatment of sleep disorders. Other effects described in the literature include its anti-inflammatory, pain modulatory, antitumor, and antioxidant properties (Blask et al., 2002; Genovese et al., 2005; Mills et al., 2005; Peres, 2005; Sofic et al., 2005; Witt-Enderby et al., 2006). The title compound is an intermediate which could yield, via the reported procedure (Attia et al., 2008), various MLT analogues which can be evaluated for their potency and selectivity for MLT receptor subtypes.

In the title compound (Fig. 1), the indole ring systems (N1/C10–C17 & N2/C1–C8) are essentially planar with maximum deviations of 0.015 (2) Å at atom C10 and C2, respectively. In addition, the indole ring systems are almost perpendicular to each other with dihedral angle of 72.17 (7)°. Bond lengths and angles are within the normal range and are comparable to those in the related structures (Narayanan et al., 2011; Deng et al., 2011).

The crystal structure is shown in Fig. 2. The molecules are linked into one dimensional zigzag chains along a-axis via N2—H1N2···O1 interactions (Table 1).

Experimental

(5-Methoxy-1H-indol-1-yl)(5-methoxy-1H-indol-2-yl)methanone (0.50 g, 156.03 mmol) was dissolved in dry THF (5 ml) and was added drop-wise to a cooled (0 °C) suspension of LiAlH₄/AlCl₃ in dry diethyl ether (prepared by a slow addition of AlCl₃ (0.32 g, 2.41 mmol) to a suspension LiAlH₄ (0.27 g, 7.13 mmol) in dry diethyl ether (15 ml) at 0 °C). The resulting reaction mixture was stirred at 0 °C for one hour and at room temperature for another one hour. The reaction was quenched by a slow addition of saturated sodium sulfate solution. The solids formed were removed by filtration, washed with chloroform (20 ml) and the combined organic phase was dried (Na₂SO₄) and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol/ammonia, 10.0:1.0:0.1) to produce the title compound as a light red powder which was recrystallized from ethanol to give single crystals (m.p. 173–174 °C).